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PHARMACOLOGY REVIEW No antiviral drugs Know both mechanisms and clinical uses Good Review Sources: First Aid, Hi-Yield Pharm, Katzung Review (drug list for Boards) Good texts: Lippincott’s, Big Katzung, Co-ops PHARMACOKINETICS KEY EQUATIONS VD = dose/concentration @ time 0 = Dose x F / AUC Clearance = KE x VD = 0.7 x VD/T1/2 Clearance ratio = CL (drug)/CL (creatinine) Css = Q/CL Loading dose = Css x VD Ct = Css (1 – e–Ket) Dosing rate Q = CL x Css CYTOCHROME P-450 • Phase I & II: Think about the O-Chem • Mechanism: – O2, NADH Redox reactions • Cyp uppers & downers – SICK EGg – Some Quompounds Really Boost Cyt P450 BUG DRUGS MECHANISM RESISTANCE USE TOXICITY INTERACTIONS PENICILLINS & CEPHALOSPORINS COMMON MECHANISM: Cell Wall (PBP) RESISTANCE: Lactamase, PBP USES: Varies by class (next few slides) TOXICITY: Allergic reactions (give Epi) INTERACTS: Probenecid & Aminoglycoside (pen) PENICILLINS • TRADITIONAL: Pens G, V – Mostly syphillis. Gm (+) are usu resistant • Narrow-spectrum: Naf, Meth, & Oxa – Staph Aureus. Some are acid stable (“oral”), others aren’t – Lactamase resistant PENICILLINS (cont’d) • WIDE-SPECTRUM – All other “-cillins” – Amp/amox: HELPS kill ENTEROCOCCI Lactamase Blockers – HEN PsEcK • LACTAMASE RESISTANT Clavulanic Acid Sulbactam – IMIPENEM: give w/ cilastatin – AZTREONAM: OK w/ pen allergy CEPHALOSPORINS • TOX: Allergy, DISULFIRAM, renal, heme – Tell your pts not to drink! • 1st Gen: Gm (+) + PEcK • 2nd Gen: HEN PEcK; no CSF • 3rd Gen: Meningitis + gonocox; CSF entry MISC. CELL WALL INHIB • Vancomycin: MRSA & Difficle. Red man sx • Bacitracin: Topical • Polymyxin: Binds LPS & hurts membranes – Did you say LPS??? Think Gm (-) PROTEIN SYNTHESIS INHIBITORS Aminoglycoside Tetracycline Chloramphenicol Erythromycin (macrolide) cLindamycin (macrolide) Lincomycin AMINOGLYCOSIDES • Are “-mycins”, but not “-thromycins” • MECHANISM: Prot Synth (30S) • RESISTANCE: Group Transferase, Bind Site, Active transport • USES: Aerobic Gm (-): Kleb & Pseudo • TOXIC: TON (= terato, oto, neuro/nephro) TETRACYCLINES • Are “-cyclines” • MECHANISM: 30S. Bacteriostatic • RESISTANCE: Inhibit entry, pump out. • USE: Rickettsia, Chlamidiae, Gm (-). VACUUM your BR. • TOX: Teeth, Bones, Renal, Liver, Photo, Superinfect. Goes to baby • INTERACTIONS: Abs w/ MILK (alkali; Ca & Mg salts) OTHER PROT SYNTH • MACROLIDES (-thromycin + clinda) – 50S methylation – Bacteroides, PCP, Toxo – Main cause of C. Difficile • CHLORAMPHENICOL – 50 S elongation block (resist: acetylation) – Enters CSF – Grey baby (hepatic metab.), CNS sx, heme tox DNA SYNTHESIS INHIBITORS SULFONAMIDES TRIMETHOPRIM QUINOLONES TRIMETHOPRIM/SULFA • SulfaMETHoxazole/Trimethoprim SULFONAMIDES • USE: Noccardia, Chlamidya, Rickettsiae; dapsone for leprosy. Specific uses also. • TOX: G6PDH (Kernicterus), renal, heme, skin, photo • INTERACTIONS: Decr P450 TRIMETHOPRIM • USE: Combo with SMX. – UTI/Prostatitis, Nocardia, PCP, URI • TOX: Folate-deficiency anemia QUINOLONES • “-floxacins” • MECHANISM: DNA-gyrase • RESISTANCE: Low. No R-plasmids – (Which is why Ciprofloxacin is a good choice for anthrax) • USE: GU & GI UTI. Not on Anaerobes • TOX: Cartilage & tendonitis. Bad for kids BUG-SPECIFIC DRUGS • TUBERCULOSIS • FUNGI • MALARIA • HELMINTHS TUBERCULOSIS FIRST LINE • INH (mycolic acid, DOC, Liver, neurotox (pyridoxine), G6PDH) • Streptomycin (see aminoglycosides) • Rifampin (DNA-dep RNA pol, red-orange fluid, renal/hep tox, p450) • Ethambutol (visual/CNS tox, red-green colorblind, use in combo) TUBERCULOSIS SECOND LINE Memorize only if you have time • Ethionamide • Aminosalicylic acid (PAS) (rarely used b/c toxic) • Pyrazinamide (Urecemia, hepatotox, polyarthalgias) • Cycloserine (cell wall synthesis, neurotoxic) ANTIFUNGALS • POLYENES: Punch holes in membrane • AZOLES: Block steroid (ergosterol) synthesis • FLUCYTOSINE: RNA synthesis (Fungi deaminate to 5-FU) • GRISEOFULVIN: Binds microtubule to block mitosis. ANTIFUNGAL: Polyenes • • • • NYSTATIN, TOLNAFTATE USE: Topical: 1 min swish & swallow. Candida (also, crypto, histo, blasto) TOX: Minimal AMPHOTERICIN USE: 1st line (wide spectrum) systemic TOX: Nephrotoxic!!! ANTIFUNGAL: AZOLES SYSTEMIC • KETOCONAZOLE: Broad Spectrum, Gynecomastia, Inhib w/ Ca, gastric pH; p450) • ITRACONAZOLE: Broad spectrum (blasto, aspergillus), no gynecomastia, Inhib w/ Ca & gastric pH • FLUCONAZOLE: Enters CSF, no gynecomastia, Inhib w/ Ca , but NOT gastric pH (Keto is an imidazole; itra & flu are triazoles) H-2 Blockers, antacids increase gastric pH ANTIFUNGAL: AZOLES TOPICAL MICONAZOLE & CLOTRIMAZOLE Topical GU/bladder tract infections Candida & dermatophytes ANTIFUNGALS: Other FLUCYTOSINE: Cryptocox & Candida, CSF. Liver, heme tox, Use with amphotericin. GRISEOFULVIN: Inhibits MT polymerization to block mitosis. Binds tightly to diseased keratin. Dermatophytes. Minimal toxicity. PARASITIC INFECTIONS Malaria: Travel hx, shivering, headache, fever x 2-3 days Ameoba: Dysentery w. eosinophilia Onchocercosis: River blindness. Scaly skin & eye lesions Giardia: Camping. Abd pain, wt loss, diarrhea ANTIMALARIALS • FM VOL • Quinine-derivatives: “-quines” – – – – – Quinine/Quinidine - Prototype. Primaquine: Kills liver form. Prophylactic Chloroquine: Stops invasion, Resistance is developing Meflo/Halo/Enpir - long T-1/2, Use w. chlq-res. Prophylaxis. All have G6PDH toxicity & GI/CNS/Heme Tox. All contraindicated in pregnancy, young kids • Doxycycline/Sulfadiazine (~TMP/SMX) – Esp. for falciparum (Chlq-res). Not in pregnancy/young kids • Pyrimethamine: DHFR block (unique to bug) ANTIHELMINTHICS • Niridazole: flukes. Activates glycogen phosphorylase & reduces egg #. Schistosomiasis • Ivernectin: River blindness (oncho), GABA agonist gives flaccid paralysis • Metronidazole: “GET on the metro”: Giardia, Entameba, Trichomoniasis. Inhibits anaerobic metabolism • Diloxanide/iodoquinol: Asx lumenal infections ANTIHELMINTHICS • Niclosamide: Tapeworms, Blocks metabolism • Mebendazole/Thiabendazole: Worms (nematodes), inhibits microtubules synthesis. • Praziquantel: Flukes, Schisto, Tapeworms; Ca entry, causing tetany • Pyrantel Pamoate: Roundworm, nicotinic agonist, spastic paralysis – Cf to piperazine, which causes FLACCID paralysis by hyperpolarizing the worm’s mm. That’s it for Bug Drugs!!!! CANCER DRUGS Show the last page of Dr. Le Breton’s handout for cancer drug mechanisms DRUG COMBINATIONS • MOPP (Mechlorethamine, Vincristine, Procarbazide, Prednisone) - Hodgkins Dz • ABVD (Doxorubicin = Adriamycin, Bleomycin, Vinblastin, Dacarbazine) - Hodkins Dz • BACOP (Bleo, Adria, Cyclophosphamide, Vincristine = Oncovin, Prednisone) - NHL, Thyroid • PVB (Cisplatin, Vinblastin, Bleo) - Testicular • CMF (Cyclophos, Methotrex, 5FU) - Breast UNUSUAL SIDE EFFECTS • BCNU: Enters CNS • Cyclophosphamide: hemorrhagic cystitis (prevent with MESNA) • Cytarabine: Neurotoxic • Methotrexate: Leukovorin rescue, Not in preg. • Vincristine: Minor BM Supp, gout, CNS tox. M-phase – But Vinblastine suppresses bone marrow • D-Actinomycin: CNS, Pneumonia • L-aspariginase - No BM Suppression • Bleomycin - Lung toxic IMMUNOSUPRESSANTS • Corticosteroids: T>B, Autoimmune dz – Prednisone, prednisolone • Cytotoxic agents – Cyclophosphamide: B>T. Not phase-specific – Azathioprine: T>B. Purine-analog. S-phase • Selective Immunosuppressants (T-cell specific) – Cyclosporine: IL2 inhibitor. Nephrotoxic; no BM sup – Tacrolimus: FK binding protein. Very toxic. – Muromonoab - CD-3 (T-cell) specific. Lung toxic. Good Luck